Lysosomal Storage Diseases (LSD) are a group of rare genetically and phenotypically heterogeneous metabolic disorders, including inherited metabolic disorders, that are characterised by defects in lysosomal function and abnormal accumulation of substances inside the lysosome (Winchester et al. 2000). Lysosomes are subcellular compartments of enzymes that facilitate the degradation of and cellular recycling of molecules. Both intracellular and extracellular substrates can be targeted to lysosomes. Several enzymes contained within the lysosome are involved in degradation. Defects in one or more of such enzymes, such as genetic mutations leading to reduced or absent production of lysosomal enzymes, result in the accumulation of within the cell of biological molecules, leading to cellular toxicity (Reece and Campbell 2002).
Typically, LSD are monogenic conditions, caused by deficiency in a single lysosomal enzyme. The incidence of specific LSD is less than 1 in 100,000 people, but as a class of diseases, the incidence is about 1 in 5,000 to 1 in 10,000 people. LSD mostly affect children who often as a result die unpredictably, such as within a few month or years from birth. Particular examples of LSD include Hurler syndrome or mucopolysaccharidosis type I (MPS-I). MPS-I is a progressive lysosomal storage disorder with systemic and central nervous system (CNS) involvement due to deficiency of α-l-iduronidase (IDUA). It has effects on the CNS and also peripherally, for example, involving cardiac defects.
Pre-clinical gene-replacement therapy studies have shown that reprogramming erythroid cells for lysosomal enzyme production leads to visceral correction of enzyme levels, for example, in a murine model of Hurler syndrome (Wang et al. 2009 and El-Amouri et al. 2014). Expression of enzyme more widely in haematopoietic cells corrects systemic and CNS pathology of MPS-I in a murine model (Visigalli et al. 2010). However, the translation of gene therapy strategies to clinical settings are currently often compromised by the levels and duration of gene expression achieved, by the breadth of cell types, tissues, organs, and organ systems that require correction and/or by the safety profile of the gene therapy vector. There are currently no cures for LSD and other related metabolic disorders, such as glycogen storage disease (GSD). This may be because treatment strategies rely on the uptake of exogenously introduced functional enzyme by affected cells, or endogenous production of functional enzyme. Although bone marrow transplantation, enzyme replacement therapy (ERT), and umbilical cord blood transplantation are used clinically to try and manage the progression of disease (Clarke et al. 2005 and Bruni et al. 2007), effectiveness of these treatment options is often limited by the availability of suitable donor tissue, and adverse immune responses such as Graft versus Host Disease (GvHD) and incomplete correction of organ pathology which has been demonstrated to be related to insufficient enzyme production (Aldenhoven et al. 2015). Thus, allogenic bone marrow transplant is not effective. Therefore, there is a need for improvements in gene-replacement therapies for LSDs and GSDs and related metabolic conditions, and more generally for other monogenic diseases.